Background & Significance. Peripheral artery disease (PAD) is a manifestation of atherosclerosis that produces progressive narrowing and occlusion of the arteries supplying the legs. PAD usually presents as claudication (leg pain and severe walking limitation), but some patients progress to limb threatening ischemia and amputation. Standard therapies for claudication have limitations, so there remains a need to develop treatments that improve limb function while decreasing the need for expensive care and procedures. Preliminary Work. We have developed and validated a porcine model of hindlimb ischemia (iliofemoral artery excision) which recapitulates key aspects of the pathophysiology of human PAD/claudication, and used it to test the efficacy of adipose-derived mesenchymal stem cells (ADMSCs). Our preliminary work shows that injection of ADMSCs into the bed of the ligated/excised iliac artery produces (i) increased arteriogenesis, (ii) enhanced muscle perfusion, and (iii) increased treadmill walking capacity in ADMSC-treated pigs compared to untreated pigs. Hypothesis, Specific Aims. Our central hypothesis is that extra-arterial delivery of autologous ADMSCs or derived exosomes will improve hemodynamic, histologic, and functional endpoints of the ischemic hindlimb with associated arteriogenesis in a porcine model of PAD. We will explore our hypothesis using a porcine model of hindlimb ischemia on a background of hypercholesterolemia and hypertension (induced with a high fat/ high fructose/ high salt diet), which mimics PAD. The central hypothesis will be explored with three Specific Aims: Aim 1. To determine whether extra-arterial administration of ADMSCs or ADMSC-derived exosomes will stimulate arteriogenesis, improve hemodynamic/ perfusion endpoints, and modulate the local inflammatory environment in a porcine model of PAD. Aim 2: To determine whether extra-arterial injection of ADMSCs or exosomes will improve ischemic myopathy and treadmill performance in a porcine model of PAD. Aim 3: To determine whether combined application of ADMSCs and monocytes will induce arteriogenesis in a perfused porcine artery system. Innovation. We will use a clinically-relevant large-animal model of PAD and novel techniques that were developed by our research group to study the physiology and histopathology of the ischemic limb. We will also utilize a derivative of porcine ADMSCs (i.e., the exosomes) which, if effective, offer numerous advantages over conventional cellular therapy. In addition, we will characterize the effect of cell-based treatments on the local inflammatory environment of the ischemic limb.